Diabetes mellitus is the most common cause of neuropathy in the United States, and almost 1/4 of those patients suffer from chronic pain. Painful diabetic neuropathy (PDN) has a significant adverse effect on quality of life;none of the available treatments reliably reduce the pain to a clinically significant degree. Herpes simplex virus (HSV) naturally targets with high efficiency to neurons of the dorsal root ganglion (DRG) from peripheral inoculation. In previous studies we have demonstrated that replication incompetent HSV-based vectors engineered to express inhibitory neurotransmitters, anti-inflammatory peptides, or the glial cell derived neurotrophic factor can reduce pain in rodent models of chronic pain. We propose a series of studies to test the hypothesis that HSV-mediated gene transfer to the DRG, achieved by subcutaneous inoculation of the vector, will provide a novel yet practical therapeutic strategy for the treatment of painful diabetic neuropathy. Five specific aims are outlined to investigate the pathogenesis of painful diabetic neuropathy and to explore the possibility that HSV-mediated gene transfer can be used to reduce mechanical hyperalgesia, mechanical allodynia, and inflammatory pain in a rodent model of diabetic neuropathy. These studies will also provide preclinical data towards the development of a gene therapy approach for PDN, a condition which is poorly controlled by available medical treatments.